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To determine the feasibility of increasing the calcium, protein and calorie intake of osteoporotic fracture patients by repeated dietary counselling delivered by a dietitian, a randomized controlled trial was conducted. Among 189 patients presenting with osteoporotic fractures to an Orthopaedics and Traumatology Department of a large regional hospital, 98 patients were randomized to the intervention group and 91 were randomized to the control group (with usual care). Intervention group received three sessions of dietary counselling with tailored made recommendations over a period of 4 months, while the control group only received dietary assessment and pamphlets on the prevention of osteoporosis. Almost all subjects in both intervention and control groups had calcium intake below the recommended level of 1000 mg at baseline. Half and 60% of subjects in both groups had total energy and protein intake below recommended levels respectively. The mean weights of control and intervention groups at baseline were 51.5 and 50.9 kg respectively, while the body mass index (BMI) were 22.6 (kg m(-2)) and 22.6 (kg m(-2)) respectively. After dietary intervention, significant increase of intake was seen in calcium intake (P = 0.0095 by t-test) in the intervention group. No significant increase was seen in protein or calorie intake. No significant change was observed in the body weight or BMI although there was a positive trend in the intervention group for all these parameters. We concluded that there was general malnutrition in Chinese elderly who presented with osteoporotic fractures. Dietary calcium could be increased by repeated professional dietary counselling. Future studies with longer duration and more objective clinical outcomes will be helpful to further demonstrate the long-term effects of dietary intervention on osteoporosis and other chronic diseases. [ABSTRACT FROM AUTHOR]

AIM: Dyslipidaemia may be a risk factor for diabetic kidney disease. We examined prospectively association between the use of statins and development of renal dysfunction in type 2 diabetes. METHODS: A consecutive cohort of 5264 diabetic patient recruited between 1996 and 2005 underwent detailed assessments. Renal dysfunction was defined as first estimated glomerular filtration rate <60 ml/min/1.73 m(2), or, the first hospitalisation with a diagnosis of renal disease as coded by the International Classification of Disease, Ninth Revision. Drug use was quantified using the proportion of exposure time from baseline to event/death/censored time, as appropriate. RESULTS: In this cohort (male: 47.3%, median age: 55 years, median duration of diabetes: 6.0 years), none had renal dysfunction at baseline. During a median follow-up period of 4.9 (quartiles: 2.77, 7.04) years, 703 patients (13.4%) developed renal dysfunction, 1275 patients (22.2%) were exposed to statins. After controlling for baseline risk factors, multivariable adjusted hazard ratio of statin use for development of renal dysfunction was 0.32 (95% CI 0.21-0.50, p<0.0001). CONCLUSION: Use of statins was associated with reduced risk of developing renal dysfunction in type 2 diabetes and this association was independent of baseline risk factors. [ABSTRACT FROM AUTHOR]

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood 1-4 . Here we use systems immunology approaches, including longitudinal multimodal single-cell analysis (surface proteins, transcriptome and V(D)J sequences) to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean, 151 days after diagnosis) and 40 age- and sex-matched control individuals who had never had COVID-19. At the baseline and independent of time after COVID-19, recoverees had elevated T cell activation signatures and lower expression of innate immune genes including Toll-like receptors in monocytes. Male individuals who had recovered from COVID-19 had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared with healthy male individuals and female individuals who had recovered from COVID-19, in part because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated prevaccination frequencies of 'virtual memory'-like CD8 + T cells poised to produce more IFNγ after IL-15 stimulation. Moreover, the expression of the repressed innate immune genes in monocytes increased by day 1 to day 28 after vaccination in recoverees, therefore moving towards the prevaccination baseline of the healthy control individuals. By contrast, these genes decreased on day 1 and returned to the baseline by day 28 in the control individuals. Our study reveals sex-dimorphic effects of previous mild COVID-19 and suggests that viral infections in humans can establish new immunological set-points that affect future immune responses in an antigen-agnostic manner., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aim: To investigate whether the American Joint Committee on Cancer (AJCC) clinical category cT2b needs to be subclassified by the type and distribution of retinoblastoma (RB) seeding., Methods: Multicentre, international registry-based data were collected from RB centres enrolled between January 2001 and December 2013. 1054 RB eyes with vitreous or subretinal seeds from 18 ophthalmic oncology centres, in 13 countries within six continents were analysed. Local treatment failure was defined as the use of secondary enucleation or external beam radiation therapy (EBRT) and was estimated with the Kaplan-Meier method., Results: Clinical category cT2b included 1054 eyes. Median age at presentation was 16.0 months. Of these, 428 (40.6%) eyes were salvaged, and 430 (40.8%) were treated with primary and 196 (18.6%) with secondary enucleation. Of the 592 eyes that had complete data for globe salvage analysis, the distribution of seeds was focal in 143 (24.2%) and diffuse in 449 (75.8%). The 5-year Kaplan-Meier cumulative globe-salvage (without EBRT) was 78% and 49% for eyes with focal and diffuse RB seeding, respectively. Cox proportional hazards regression analysis confirmed a higher local treatment failure risk with diffuse seeds as compared with focal seeds (hazard rate: 2.8; p<0.001). There was insufficient evidence to prove or disprove an association between vitreous seed type and local treatment failure risk(p=0.06)., Conclusion: This international, multicentre, registry-based analysis of RB eyes affirmed that eyes with diffuse intraocular distribution of RB seeds at diagnosis had a higher risk of local treatment failure when compared with focal seeds. Subclassification of AJCC RB category cT2b into focal vs diffuse seeds will improve prognostication for eye salvage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure. Plasma renin activities (PRA) and plasma aldosterone concentrations (PAC) are biomarkers related to RAAS. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based measurements for PRA and PAC have become popular. Method-specific reference intervals (RIs) are required., Methods: Routine PRA and PAC services in a Hong Kong teaching hospital were based on LC-MS/MS methods. PRA and PAC RIs were developed for normotensive subjects and essential hypertensive (EH) patients. Healthy volunteers were recruited to establish normotensive RIs. PRA and PAC results of hypertensive patients with urine aldosterone tests for primary aldosteronism (PA) screening were retrieved from the laboratory information system. Patients without PA were included. Patients with secondary hypertension and patients on medications affecting the RAAS were excluded. The central 95% RIs were established based on the recommendations of the Clinical and Laboratory Standards Institute guideline C28-A3., Results: PRA and PAC of 170 normotensive volunteers and 362 EH patients were analysed. There was no sex-specific difference in PRA and PAC for normotensive and EH reference subjects. Differences for PRA and PAC were noted between normotensive subjects aged below 45 and their older counterparts. However, such a difference was only identified for PRA but not PAC in EH patients. Age-specific RIs were established accordingly., Conclusions: This study presented age-specific LC-MS/MS RIs of PRA and PAC for both normotensive and EH populations for local Chinese in Hong Kong., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: To evaluate presenting features, tumor size, and treatment methods for risk of metastatic death due to advanced intraocular retinoblastoma (RB)., Design: International, multicenter, registry-based retrospective case series., Participants: A total of 1841 patients with advanced RB., Methods: Advanced RB was defined by 8th edition American Joint Committee on Cancer (AJCC) categories cT2 and cT3 and new AJCC-Ophthalmic Oncology Task Force (OOTF) Size Groups (1: < 50% of globe volume, 2: > 50% but < 2/3, 3: > 2/3, and 4: diffuse infiltrating RB). Treatments were primary enucleation, systemic chemotherapy with secondary enucleation, and systemic chemotherapy with eye salvage., Main Outcome Measures: Metastatic death., Results: The 5-year Kaplan-Meier cumulative survival estimates by patient-level AJCC clinical subcategories were 98% for cT2a, 96% for cT2b, 88% for cT3a, 95% for cT3b, 92% for cT3c, 84% for cT3d, and 75% for cT3e RB. Survival estimates by treatment modality were 96% for primary enucleation, 89% for systemic chemotherapy and secondary enucleation, and 90% for systemic chemotherapy with eye salvage. Risk of metastatic mortality increased with increasing cT subcategory (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality in categories cT3c (glaucoma, hazard ratio [HR], 4.9; P = 0.011), cT3d (intraocular hemorrhage, HR, 14.0; P < 0.001), and cT3e (orbital cellulitis, HR, 19.6; P < 0.001) than in category cT2a and with systemic chemotherapy with secondary enucleation (HR, 3.3; P < 0.001) and eye salvage (HR, 4.9; P < 0.001) than with primary enucleation. The 5-year Kaplan-Meier cumulative survival estimates by AJCC-OOTF Size Groups 1 to 4 were 99%, 96%, 94%, and 83%, respectively. Mortality from metastatic RB increased with increasing Size Group (P < 0.001). Cox proportional hazards regression analysis revealed that patients with Size Group 3 (HR, 10.0; P = 0.002) and 4 (HR, 41.1; P < 0.001) had a greater risk of metastatic mortality than Size Group 1., Conclusions: The AJCC-RB cT2 and cT3 subcategories and size-based AJCC-OOTF Groups 3 (> 2/3 globe volume) and 4 (diffuse infiltrating RB) provided a robust stratification of clinical risk for metastatic death in advanced intraocular RB. Primary enucleation offered the highest survival rates for patients with advanced intraocular RB., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

OMiCC (OMics Compendia Commons) is a biologist-friendly web platform that facilitates data reuse and integration. Users can search over 40,000 publicly available gene expression studies, annotate and curate samples, and perform meta-analysis. Since the initial publication, we have incorporated RNA-seq datasets, compendia sharing, RESTful API support, and an additional meta-analysis method based on random effects. Here, we provide a step-by-step guide for using OMiCC. For complete details on the use and execution of this protocol, please refer to Shah et al. (2016)., Competing Interests: The authors declare no competing interests., (© 2022.)

Although the automatic speech recognition (ASR) technology is increasingly used for commercial purposes, its impact on language learning has not been extensively studied. Underpinned by the sociocultural theory, the present work examined the effects of leveraging ASR technology to support English vocabulary learning in a tertiary flipped setting. A control group and an experimental group of college students participated in a 14-week study. Both groups had their English classes in a flipped fashion, but the experimental group was assigned with ASR-assisted oral tasks for pre-class self-learning. The pre- and post-intervention in-class task performance of both groups was audio-recorded and transcribed for data analysis. The triadic complexity-accuracy-fluency (CAF) framework was adopted to evaluate the participants' vocabulary learning. The between- and within-subjects effects were examined mainly through procedures of MANCOVA and mixed-design repeated measures ANCOVA. Results showed that on all the metrics of lexical complexity and speed fluency, the experimental group outperformed the control group, and had significant growth over time. On the other hand, the control group only improved significantly overtime on the G-index. On lexical accuracy, there was no significant difference between the two groups, and the within-subjects effect was not significant for either group. The findings lent some support to Skehan's Trade-off Hypothesis and discussions were conducted regarding the triarchic CAF framework., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Jong, Wu, Shen, Chai, Lau and Huang.)

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

Saliva has become an attractive body fluid for on-site, remote, and real-time monitoring of oral and systemic health. At the same time, the scientific community needs a saliva-centered information platform that keeps pace with the rapid accumulation of new data and knowledge by annotating, refining, and updating the salivary proteome catalog. We developed the Human Salivary Proteome (HSP) Wiki as a public data platform for researching and retrieving custom-curated data and knowledge on the saliva proteome. The HSP Wiki is dynamically compiled and updated based on published saliva proteome studies and up-to-date protein reference records. It integrates a wide range of available information by funneling in data from established external protein, genome, transcriptome, and glycome databases. In addition, the HSP Wiki incorporates data from human disease-related studies. Users can explore the proteome of saliva simply by browsing the database, querying the available data, performing comparisons of data sets, and annotating existing protein entries using a simple, intuitive interface. The annotation process includes both user feedback and curator committee review to ensure the quality and validity of each entry. Here, we present the first overview of features and functions the HSP Wiki offers. As a saliva proteome-centric, publicly accessible database, the HSP Wiki will advance the knowledge of saliva composition and function in health and disease for users across a wide range of disciplines. As a community-based data- and knowledgebase, the HSP Wiki will serve as a worldwide platform to exchange salivary proteome information, inspire novel research ideas, and foster cross-discipline collaborations. The HSP Wiki will pave the way for harnessing the full potential of the salivary proteome for diagnosis, risk prediction, therapy of oral and systemic diseases, and preparedness for emerging infectious diseases.Database URL: https://salivaryproteome.nidcr.nih.gov/.

The present study validated the general extended technology acceptance model for e-learning (GETAMEL) with the survey data from the English as a foreign language (EFL) online class during the novel coronavirus lockdown period. A total of 678 undergraduates participated in the survey. Structural equation modeling was employed to analyze the data. The results showed that the influence of perceived usefulness of students on their intentional behavior to use the online learning system was not mediated by their attitude, indicating a very limited role of attitude toward technology in the model. Enjoyment and self-efficacy had no significant effects on the internal constructs, raising theoretical concerns on the applicability of this general model into specific contexts. In addition, we found that experience might be a moderator rather than an antecedent of the internal constructs in the model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiang, Jong, Lau, Meng, Chai and Chen.)

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56 dim CD16 hi NK cells linked positively to circulating interleukin (IL)-15. CD8 + T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

The Scholl-type cyclodehydrogenation, generating up to four cycloheptatriene rings around a fenestrindane core, leads to novel, saddle-shaped polyaromatic hydrocarbon derivatives. In this article, we present the results of in-depth experimental and computational work on the oxidative cyclization of various 1,4,9,12-tetraarylfenestrindanes. In particular, the kinetic control of the four-step cyclization of the electronically activated tetrakis(3,4-dimethoxyphenyl) derivative is elucidated. The reasons for the exclusive emergence of one single among the three possible doubly cyclized intermediates and for the nonappearance of the singly and triply cyclized intermediates are clarified. In addition, the origin of the concomitant bridgehead hydroxylation is studied. The reactivity of a set of fifteen symmetrically and unsymmetrically substituted 1,4,9,12-tetraarylfenestrindanes towards Scholl-type cyclodehydrogenation is presented, pinpointing the structural factors that underlie this reaction and demonstrating the potential and limitations of this synthetic approach. A particularly surprising finding of this study is that the electronically nonactivated 1,4,9,12-tetraphenylfenestrindane can also undergo the fourfold Scholl-type cyclization process and can be transformed into the parent saddle hydrocarbon., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cell-to-cell variation in gene expression and the propagation of such variation (PoV or "noise propagation") from one gene to another in the gene network, as reflected by gene-gene correlation across single cells, are commonly observed in single-cell transcriptomic studies and can shape the phenotypic diversity of cell populations. While gene network "rewiring" is known to accompany cellular adaptation to different environments, how PoV changes between environments and its underlying regulatory mechanisms are less understood. Here, we systematically explored context-dependent PoV among genes in human macrophages, utilizing different cytokines as natural perturbations of multiple molecular parameters that may influence PoV. Our single-cell, epigenomic, computational, and stochastic simulation analyses reveal that environmental adaptation can tune PoV to potentially shape cellular heterogeneity by changing parameters such as the degree of phosphorylation and transcription factor-chromatin interactions. This quantitative tuning of PoV may be a widespread, yet underexplored, property of cellular adaptation to distinct environments., (Copyright © 2017. Published by Elsevier Inc.)

New technologies have been propelling dramatic increases in the volume and diversity of large-scale public data, which can potentially be reused to answer questions beyond those originally envisioned. However, this often requires computational and statistical skills beyond the reach of most bench scientists. The development of educational and accessible computational tools is thus critical, as are crowdsourcing efforts that utilize the community's expertise to curate public data for hypothesis generation and testing. Here we review the history of public-data reuse and argue for greater incorporation of computational and statistical sciences into the biomedical education curriculum and the development of biologist-friendly crowdsourcing tools. Finally, we provide a resource list for the reuse of public data and highlight an illustrative crowdsourcing exercise to explore public gene-expression data of human autoimmune diseases and corresponding mouse models. Through education, tool development, and community engagement, immunologists will be poised to transform public data into biological insights., (Copyright © 2016. Published by Elsevier Inc.)

Background : The proliferation of publicly accessible large-scale biological data together with increasing availability of bioinformatics tools have the potential to transform biomedical research. Here we report a crowdsourcing Jamboree that explored whether a team of volunteer biologists without formal bioinformatics training could use OMiCC, a crowdsourcing web platform that facilitates the reuse and (meta-) analysis of public gene expression data, to compile and annotate gene expression data, and design comparisons between disease and control sample groups. Methods: The Jamboree focused on several common human autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), type I diabetes (DM1), and rheumatoid arthritis (RA), and the corresponding mouse models. Meta-analyses were performed in OMiCC using comparisons constructed by the participants to identify 1) gene expression signatures for each disease (disease versus healthy controls at the gene expression and biological pathway levels), 2) conserved signatures across all diseases within each species (pan-disease signatures), and 3) conserved signatures between species for each disease and across all diseases (cross-species signatures). Results: A large number of differentially expressed genes were identified for each disease based on meta-analysis, with observed overlap among diseases both within and across species. Gene set/pathway enrichment of upregulated genes suggested conserved signatures (e.g., interferon) across all human and mouse conditions. Conclusions: Our Jamboree exercise provides evidence that when enabled by appropriate tools, a "crowd" of biologists can work together to accelerate the pace by which the increasingly large amounts of public data can be reused and meta-analyzed for generating and testing hypotheses. Our encouraging experience suggests that a similar crowdsourcing approach can be used to explore other biological questions., Competing Interests: Competing interests: No competing interests were disclosed.

This systematic review and meta-analysis is to evaluate the risk of development of concomitant strabismus due to refractive errors. Eligible studies published from 1946 to April 1, 2016 were identified from MEDLINE and EMBASE that evaluated any kinds of refractive errors (myopia, hyperopia, astigmatism and anisometropia) as an independent factor for concomitant exotropia and concomitant esotropia. Totally 5065 published records were retrieved for screening, 157 of them eligible for detailed evaluation. Finally 7 population-based studies involving 23,541 study subjects met our criteria for meta-analysis. The combined OR showed that myopia was a risk factor for exotropia (OR: 5.23, P = 0.0001). We found hyperopia had a dose-related effect for esotropia (OR for a spherical equivalent [SE] of 2-3 diopters [D]: 10.16, P = 0.01; OR for an SE of 3-4D: 17.83, P < 0.0001; OR for an SE of 4-5D: 41.01, P < 0.0001; OR for an SE of ≥5D: 162.68, P < 0.0001). Sensitivity analysis indicated our results were robust. Results of this study confirmed myopia as a risk for concomitant exotropia and identified a dose-related effect for hyperopia as a risk of concomitant esotropia.

CXCL8 (also known as interleukin-8 or IL-8) is a proinflammatory chemokine that not only modulates the inflammatory and immune responses, but whose upregulation is often associated with diseases including various types of cancer. Although numerous ligands for G protein-coupled receptors (GPCRs) have been shown to stimulate the production of CXCL8, the specificity of the G protein signal remains undefined. By expressing the constitutively active Gα subunits in HEK293 cells, CXCL8 production was herein demonstrated to be most effectively stimulated by Gαq family members, while those of Gαs and Gα12 elicited much weaker activities, and Gαi being totally ineffective. However, in cell lines such as HepG2, HeLa, and MCF-7 that endogenously express Gβγ-responsive phospholipase Cβ isoforms (PLCβ2/3), activation of the Gi-coupled α2-adrenoceptor significantly stimulated CXCL8 production. This Gi-induced CXCL8 production was apparently mediated via specific Gβγ dimers and required the presence of PLCβ2/3. Co-activation of Gi-coupled α2-adrenoceptor and Gq-coupled bradykinin receptor resulted in a synergistic CXCL8 production, with Gβγ-responsive PLCβ2/3, Src, ERK, and STAT3 serving as critical signaling intermediates. The treatment of HepG2 and B-10 endothelial cells with bradykinin stimulated CXCL8 production and cell proliferation. Interestingly, the latter response was driven by CXCL8 autocrine signaling because it was abolished by SB225002, an antagonist that prevents CXCL8 from binding to CXCR2. Collectively, our results provide a mechanistic basis for various G protein subfamilies to regulate the production of CXCL8, which may then lead to paracrine and/or autocrine signaling with major implications in both normal physiology and pathophysiological conditions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In a recent study, Chung et al. report the development of a high-dimensional approach to assess humoral responses to immune perturbation that goes beyond antibody neutralization and titers. This approach enables the identification of potentially novel correlates and mechanisms of protective immunity to HIV vaccination, thus offering a glimpse of how dense phenotyping of serological responses coupled with bioinformatics analysis could lead to much-sought-after markers of protective vaccination responses., (Published by Elsevier Ltd.)

Aim: Understanding factors that contribute to treatment delay would inform early detection and intervention strategies in psychotic disorders. However, existing data were mixed and primarily conducted among early-onset young patients. We examined duration of untreated psychosis (DUP) and its clinical and sociodemographic correlates in a large cohort of adult-onset patients with psychosis., Methods: A total of 360 patients with first-onset psychosis aged 26-55 years were recruited consecutively as part of a controlled study of an early psychosis intervention service in Hong Kong Chinese. Demographic, sociodemographic and clinical characteristics relating to DUP were assessed within 4 months of onset., Results: The population had a mean onset age of 36.6 years (SD = 8.7). The mean and median DUP were 515 days (SD = 1091) and 93 days (inter-quartile range from 20 to 382.3), respectively. Multivariate regression analysis suggested that insidious mode of onset, hospitalization, a diagnosis of schizophrenia, poorer insight and younger age at onset significantly prolonged DUP. DUP was not related to premorbid functioning, family involvement during help seeking and living alone., Conclusions: The initial period of untreated psychosis is determined by multiple factors. Whether family involvement is considered a kind of social support in shortening or prolonging DUP needs further examination. Local early intervention program for psychosis should take reference from these findings when formulating personalized plans to reduce delay., (© 2013 Wiley Publishing Asia Pty Ltd.)

Purpose: To evaluate and compare the effectiveness of scleral fixation SR and LR union suture and nonscleral fixation union suture for the treatment of myopic strabismus fixus., Methods: Retrospective review of 32 eyes of 22 patients with myopic strabismus fixus who had undergone union suture of superior rectus (SR) and lateral rectus (LR) with or without scleral fixation, and follow-up longer than 6 months at Hong Kong Eye Hospital from 2006 to 2013. Surgical techniques and outcomes in terms of ocular alignment are analyzed., Results: There is significant overall improvement both in postoperative angle of esodeviation (P < 0.01) and postoperative range of movement (P = 0.042). Comparing between the sclera fixation group (11 eyes) versus nonscleral fixation group (21 eyes), the postoperative horizontal deviation, the postoperative vertical deviation, successful outcome, and the change in horizontal deviation were not significantly different (P > 0.05)., Conclusions: Union suture of SR and LR is an effective procedure in correcting myopic strabismus fixus. Fixation of the union suture to the sclera does not improve surgical outcome.

Background: The Early Development Instrument (EDI) is a comprehensive instrument used to assess school readiness in preschool children. This study was carried out to evaluate the psychometric properties of the Chinese version of the EDI (CEDI) in Hong Kong., Methods: One hundred and sixty-seven children were purposefully sampled from kindergartens in two districts with very different socioeconomic statuses. The CEDI was assessed for concurrent validity, internal consistency and test-retest reliability. The developmental vulnerability identified using the CEDI scores was further examined in relation to the socioeconomic status of the district and family., Results: The CEDI displayed adequate internal consistency, with Cronbach's alphas ranging from 0.70 to 0.95 on its five domains. Concurrent validity was supported by moderate and significant correlations (0.25 to 0.49) on the relevant domains between the CEDI and a comparable measure. The level of test-retest reliability was good, with a kappa statistic of 0.89. In general, girls outperformed boys, particularly in the social, emotional and communication/general knowledge domains. After controlling for the uneven distribution of sex, children from socioeconomically disadvantaged districts and families were found to be at greater risk of developmental vulnerability than their more advantaged counterparts., Conclusion: The evidence gathered in this study supports the CEDI's use as a valid and reliable instrument in assessing school readiness and identifying developmentally vulnerable children in Chinese populations. Its preliminary findings on the socioeconomic gradients of child development suggest that the CEDI is a promising tool for leveraging evidence-based, context-sensitive policies and practices to foster the development of all children.

Background: In type 2 diabetes, tight glycaemic control lowers the risk of diabetic complications, but it remains uncertain whether variability of glycaemia influences outcomes. We examined the association of glycated haemoglobin (HbA1c ) variability with incident chronic kidney disease and cardiovascular disease in a prospective cohort of 8439 Chinese patients with type 2 diabetes recruited from 1994 to 2007., Methods: Intrapersonal mean and SD of serially measured HbA1c were calculated. Chronic kidney disease was defined as estimated glomerular filtration rate <60 ml/min per 1.73 m². Cardiovascular disease was defined as events of ischemic heart disease, heart failure, ischemic stroke or peripheral vascular disease., Results: Over a median follow-up period of 7.2 years, 19.7 and 10.0% of patients developed chronic kidney disease and cardiovascular disease, respectively. Patients who progressed to chronic kidney disease had higher mean HbA1c (7.8 ± 1.3% vs 7.4 ± 1.2%, p < 0.001) and SD (1.0 ± 0.8% vs 0.8 ± 0.6%, p < 0.001) than nonprogressors. Similarly, patients who developed cardiovascular disease had higher mean HbA1c (7.7 ± 1.3% vs 7.4 ± 1.2%, p < 0.001) and SD (1.4 ± 1.1% vs 1.1 ± 0.8%, p < 0.001) than patients who did not develop cardiovascular disease. By using multivariate-adjusted Cox regression analysis, adjusted SD was associated with incident chronic kidney disease and cardiovascular disease with corresponding hazard ratios of 1.16 (95% CI 1.11-1.22), p < 0.001) and 1.27 (95% CI 1.15-1.40, p < 0.001), independent of mean HbA1c and other confounding variables., Conclusions: Long-term glycaemic variability expressed by SD of HbA1c predicted development of renal and cardiovascular complications., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Depression is known to be associated with premature mortality and cardiovascular disease (CVD) in type 2 diabetes, although there is a paucity of similar data in Chinese population. In this study, we examined the risk association of major depression with premature mortality and CVD in a hospital clinic-based cohort., Methods: In a prospective cohort of 7835 Hong Kong Chinese with type 2 diabetes but without CVD at baseline, 153 patients were diagnosed with major depression by psychiatrists in public hospitals. After a median follow-up period of 7.4 years, 827 patients died and 829 patients developed CVD mainly due to stroke (n=384). We used Cox proportional hazard regression to obtain the hazard ratio (HR, 95% confidence interval, CI) of depression for the risk of mortality and CVD., Results: Depressed patients were younger (51.6 versus 56.6 years, p<0.001), more likely to be female (78.4% versus 53.0%, p<0.001), had higher LDL-cholesterol (3.2 versus 3.0 mmol/L, p=0.038) at baseline and longer hospitalization stays per year (median:0.8 nights per 100-person-years versus 0.1 nights per 100-person-years, p<0.001). After adjusting for conventional risk factors, depression independently predicted CVD [HR=2.18(95% CI=1.45-3.27)], mainly due to stroke [HR=3.55(95% CI=2.15-5.84)]., Limitations: The young age and small sample size of patients with depression did not give sufficient power to confirm risk association of depression with premature mortality and myocardial infarction., Conclusions: In Chinese type 2 diabetic patients, depression was associated with a 2-3 fold increase in the risk of incident CVD, especially stroke., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Protein kinase D (PKD) constitutes a novel family of serine/threonine protein kinases implicated in fundamental biological activities including cell proliferation, survival, migration, and immune responses. Activation of PKD in these cellular activities has been linked to many extracellular signals acting through antigen receptor engagement, receptor tyrosine kinases, as well as G protein-coupled receptors. In the latter case, it is generally believed that the Gα subunits of the Gq family are highly effective in mediating PKD activation, whereas little is known with regard to the ability of Gβγ dimers and other Gα subunits to stimulate PKD. It has been suggested that the interaction between Gβγ and the PH domain of PKD, or the Gβγ-induced PLCβ/PKC activity is critical for the induction of PKD activation. However, the relative contribution of these two apparently independent events to Gβγ-mediated PKD activation has yet to be addressed., Results: In this report, we demonstrate that among various members in the four G protein families, only the Gα subunits of the Gq family effectively activate all the three PKD isoforms (PKD1/2/3), while Gα subunits of other G protein families (Gs, Gi, and G12) are ineffective. Though the Gα subunits of Gi family are unable to stimulate PKD, receptors linked to Gi proteins are capable of triggering PKD activation in cell lines endogenously expressing (HeLa cells and Jurkat T-cells) or exogenously transfected with (HEK293 cells) Gβγ-sensitive PLCβ2/3 isoforms. This indicates that the Gi-mediated PKD activation is dependent on the released Gβγ dimers upon stimulation. Further investigation on individual Gβγ combinations (i.e. Gβ1 with Gγ1-13) revealed that, even if they can stimulate the PLCβ activity in a comparable manner, only those Gβ1γ dimers with γ2, γ3, γ4, γ5, γ7, and γ10 can serve as effective activators of PKD. We also demonstrated that Gi-mediated PKD activation is essential for the SDF-1α-induced chemotaxis on Jurkat T-cells., Conclusions: Our current report illustrates that Gβγ dimers from the Gi proteins may activate PKD in a PLCβ2/3-dependent manner, and the specific identities of Gγ components within Gβγ dimers may determine this stimulatory action.

Lysosomes are subcellular organelles playing a vital role in the endocytosis process of the cell. Lysosomal acidity is an important factor in assuring proper functioning of the enzymes within the organelle, and can be assessed by labeling the lysosomes with pH-sensitive fluorescence probes. To enhance our understanding of the acidification mechanisms, the goal of this work is to develop a method that can accurately detect and characterize the acidity of each lysosome captured in ratiometric fluorescence images. We present an algorithm that utilizes the h -dome transformation and reconciles spots detected independently from two wavelength channels. We evaluated our algorithm using simulated images for which the exact locations were known. The h -dome algorithm achieved an f -score as high as 0.890. We also computed the fluorescence ratios from lysosomes in live HeLa cell images with known lysosomal pHs. Using leave-one-out cross-validation, we demonstrated that the new algorithm was able to achieve much better pH prediction accuracy than the conventional method.

Melatonin receptors have previously been shown to elicit cellular signaling through the hematopoietic-specific G protein, G(16) . In the present study, we show that this functional coupling elicited biphasic stimulatory phosphorylation on STAT3 in recombinant MT(1) /Gα(16) cells and native Jurkat T cells (endogenously expressing MT(1) and Gα(16) ), with maximal Ser(727) phosphorylation occurring at 15min, while marked Tyr(705) phosphorylation became detectable only upon agonist treatment for 4 hr or more. By employing signal transducer and activator of transcription 3 (STAT3) phosphorylation-resistant mutants (STAT3-Y705F and STAT3-S727A), we further showed that the receptor-mediated STAT3 phosphorylations at Ser(727) and Tyr(705) were independent of each other. Results obtained from fractionation of 2-IMT-induced cells revealed that the Ser(727) and Tyr(705) phosphorylations were spatially distinct, with the former mainly situated in mitochondria and cytosol, while the latter was predominantly located in the nucleus. Further experiments revealed that the agonist-induced STAT3 phosphorylation at Tyr(705) was significantly suppressed by pretreatment with cycloheximide (a ribosome inhibitor), suggesting that de novo protein synthesis might play a critical role for this response. Using conditioned media obtained from 2-IMT-treated MT(1) /Gα(16) cells, multiplex immunoassays revealed that prolonged agonist treatment led to elevated productions of IL-6, GM-CSF and CXCL-8. Antibody against IL-6, but not those for GM-CSF and CXCL-8, effectively abolished the agonist-induced STAT3 Tyr(705) phosphorylation, suggesting the involvement of IL-6 in melatonin receptor-mediated STAT3 activation. Our results demonstrate that melatonin receptor/Gα(16) coupling is capable of triggering the production of cytokines including IL-6, and this autocrine loop may account for the subsequent STAT3 phosphorylation at Tyr(705) ., (© 2011 John Wiley & Sons A/S.)

Objective: Type 2 diabetes is the leading cause of end-stage renal disease worldwide. Aside from hyperglycemia and hypertension, other metabolic factors may determine renal outcome. We examined risk associations of metabolic syndrome with new onset of chronic kidney disease (CKD) in 5,829 Chinese patients with type 2 diabetes enrolled between 1995 and 2005., Research Design and Methods: Metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of obesity. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula modified for the Chinese population. New onset of CKD was defined as eGFR <60 ml/min per 1.73 m(2) at the time of censor. Subjects with CKD at baseline were excluded from the analysis., Results: After a median follow-up duration of 4.6 years (interquartile range: 1.9-7.3 years), 741 patients developed CKD. The multivariable-adjusted hazard ratio (HR) of CKD was 1.31 (95% CI 1.12-1.54, P = 0.001) for subjects with metabolic syndrome compared with those without metabolic syndrome. Relative to subjects with no other components of metabolic syndrome except for diabetes, those with two, three, four, and five metabolic syndrome components had HRs of an increased risk of CKD of 1.15 (0.83-1.60, P = 0.407) 1.32 (0.94-1.86, P = 0.112), 1.64 (1.17-2.32, P = 0.004), and 2.34 (1.54-3.54, P < 0.001), respectively. The metabolic syndrome traits of central obesity, hypertriglyceridemia, hypertension, and low BMI were independent predictors for CKD., Conclusions: The presence of metabolic syndrome independently predicts the development of CKD in subjects with type 2 diabetes.

Purpose: To describe the clinical features and outcomes among contact lens wearers with Fusarium keratitis., Methods: A retrospective observational review of all cases of culture-proven Fusarium keratitis among contact lens wearers from three hospitals in Hong Kong Island were included. The clinical features, hygiene habits, and clinical outcomes were reviewed., Results: Sixteen patients (17 eyes) were diagnosed with Fusarium keratitis associated with contact lens wear. One patient had bilateral involvement. Six patients had a central lesion; four had paraxial lesions; one had paraxial and peripheral lesions; and the rest had peripheral lesions. Ten (62.5%) patients reported using ReNu multipurpose cleaning solution. Most patients had poor contact lens hygiene habits. One patient required systemic antifungal treatment. No surgical intervention was required in any of the patients., Conclusions: The clinical features of Fusarium keratitis in contact lens wearers can be variable. Although fungal infection is reported rarely, clinicians should maintain a high index of suspicion for it when examining patients with contact lens-associated microbial keratitis. Education on proper contact lens care should be reinforced. Early and appropriate treatment may lead to satisfactory visual outcomes.

Background: The goal of the gene normalization task is to link genes or gene products mentioned in the literature to biological databases. This is a key step in an accurate search of the biological literature. It is a challenging task, even for the human expert; genes are often described rather than referred to by gene symbol and, confusingly, one gene name may refer to different genes (often from different organisms). For BioCreative II, the task was to list the Entrez Gene identifiers for human genes or gene products mentioned in PubMed/MEDLINE abstracts. We selected abstracts associated with articles previously curated for human genes. We provided 281 expert-annotated abstracts containing 684 gene identifiers for training, and a blind test set of 262 documents containing 785 identifiers, with a gold standard created by expert annotators. Inter-annotator agreement was measured at over 90%., Results: Twenty groups submitted one to three runs each, for a total of 54 runs. Three systems achieved F-measures (balanced precision and recall) between 0.80 and 0.81. Combining the system outputs using simple voting schemes and classifiers obtained improved results; the best composite system achieved an F-measure of 0.92 with 10-fold cross-validation. A 'maximum recall' system based on the pooled responses of all participants gave a recall of 0.97 (with precision 0.23), identifying 763 out of 785 identifiers., Conclusion: Major advances for the BioCreative II gene normalization task include broader participation (20 versus 8 teams) and a pooled system performance comparable to human experts, at over 90% agreement. These results show promise as tools to link the literature with biological databases.

We introduce the first meta-service for information extraction in molecular biology, the BioCreative MetaServer (BCMS; http://bcms.bioinfo.cnio.es/). This prototype platform is a joint effort of 13 research groups and provides automatically generated annotations for PubMed/Medline abstracts. Annotation types cover gene names, gene IDs, species, and protein-protein interactions. The annotations are distributed by the meta-server in both human and machine readable formats (HTML/XML). This service is intended to be used by biomedical researchers and database annotators, and in biomedical language processing. The platform allows direct comparison, unified access, and result aggregation of the annotations.

Purpose: To describe the changing pattern of clinical features and microbiology of contact lens-associated microbial keratitis in Hong Kong., Methods: This is a retrospective observational case series of patients diagnosed with contact lens-associated microbial keratitis between July 2004 and April 2005 and between July 2005 and April 2006. Patients who wore contact lenses solely for the correction of refractive error and who were seen at Queen Mary Hospital were included in the study. The clinical characteristics, microbiology, and visual outcomes were compared., Results: There were 14 cases between July 2004 and April 2005. Most cases had an axial lesion (eight) or paraxial lesions (four). Corneal scrapings were positive in seven (50%) patients, among whom six showed Pseudomonas aeruginosa and one showed Serratia marcescens as the pathogens. Contact lens storage cases yielded polymicrobial growth in two cases. For the more recent cohort, Fusarium species had been identified as the dominant pathogen, and most (60%) contact lens storage cases showed polymicrobial growth., Conclusions: There has been an increased number of cases of contact lens-associated fungal keratitis recently. Fusarium species and polymicrobial growth are becoming more dominant.

Erdheim-Chester disease is a rare, idiopathic, non-Langerhans' cell, histiocytic disorder. To our knowledge this is only the second case of Erdheim-Chester disease reported in the Chinese population. We describe a 45-year-old woman presenting with unilateral proptosis and periorbital xanthelasma. Histopathological examination revealed a xanthogranulomatous lesion expressing CD68, but negative for S100 protein, CD1a, CD3, or CD20. Systemic involvement was evident on bone scanning, and involvement of the thorax and abdominal aorta was seen on computed tomography. Despite treatment with systemic steroids, immunosuppressants, chemotherapy and interferon, progressive deterioration occurred. Our patient's clinical course was consistent with reports in the literature. Unfortunately, our patient developed neutropenic fever and died from septicaemic shock. Although Erdheim-Chester disease is a rare entity, especially in the Chinese population, an unusual presentation with orbital masses and bilateral xanthelasma, associated with systemic features, should raise the suspicion of this serious and potentially fatal disease.

The influence of the phytoplankton-specific organic compound glycolate on bacterial community structure was examined during the 2004 spring phytoplankton bloom (February to April) in Dabob Bay in Washington. The diversity of the bacteria able to utilize glycolate during the phytoplankton bloom was determined using previously developed PCR primers to amplify the gene for the D subunit of glycolate oxidase (glcD). Many of the glcD sequences obtained represented novel sequences that appeared to be specific to marine environments. Overall, the glcD sequence diversity decreased as the phytoplankton bloom progressed. Phylotype-specific glcD quantitative PCR primers were designed for the six most commonly detected glcD phylotypes that represented distinct phylogenetic groups of heterotrophic bacteria. Three patterns of phylotype abundance were detected: four phylotypes were most abundant during the onset of the bloom; the abundance of one phylotype increased as the bloom progressed; and one phylotype was abundant throughout the bloom. Quantitative reverse transcriptase PCR with the same phylotype-specific primers was used to determine the levels of day and night glcD RNA transcription over the course of the bloom. glcD transcripts, when detectable, were always more abundant in the day than at night for each phylotype, suggesting that the bacteria responded to the glycolate produced by phytoplankton during the day. The nearly constant low in situ glycolate concentrations suggested that bacteria rapidly utilized the available glycolate. This study provided evidence for direct phytoplankton-bacterium interactions and the resulting succession in a single functional group of marine bacteria.

The ability to identify gene mentions in text and normalize them to the proper unique identifiers is crucial for "down-stream" text mining applications in bioinformatics. We have developed a rule-based algorithm that divides the normalization task into two steps. The first step includes pattern matching for gene symbols and an approximate term searching technique for gene names. Next, the algorithm measures several features based on morphological, statistical, and contextual information to estimate the level of confidence that the correct identifier is selected for a potential mention. Uniqueness, inverse distance, and coverage are three novel features we quantified. The algorithm was evaluated against the BioCreAtIvE datasets. The feature weights were tuned by the Nealder-Mead simplex method. An F-score of .7622 and an AUC (area under the recall-precision curve) of .7461 were achieved on the test data using the set of weights optimized to the training data.

Of eight laboratory cultures of marine gamma- and alpha-Proteobacteria tested, growth on glycolate as a sole carbon source was detected for only three species: Pseudomonas stutzeri, Oceanimonas doudoroffii and Roseobacter sp. isolate Y3F. Degenerate polymerase chain reaction (PCR) primers were designed to amplify glcD, which encodes the D-subunit of the enzyme glycolate oxidase; glcD could be amplified only from those cultures that grew on glycolate. The PCR primers were used to explore glcD diversity in four field samples collected from different ocean environments: an Atlantic Gulf Stream Ring, sampled above and below the thermocline and two Pacific coastal sites, Parks Bay and San Juan Channel, WA. Environmental glcD sequences belonged to six major bacterial phylogenetic groups, with most sequences forming novel clades with no close relatives. Different patterns of glcD diversity were observed within and between the two nutrient regimes. Comparison of glcD and 16S rDNA diversity and analyses of available bacterial genomes and a metgenomic library from the Sargasso Sea show that glycolate-utilizing potential exists in only a subset of bacteria. Glycolate is produced in marine environments mainly by phytoplankton. Examination of glcD diversity will aid in understanding the influence of phytoplankton on bacterial community structure.

A primary care group diabetes care program using telemedicine was developed and its feasibility and acceptability were tested in 22 subjects with Type 2 diabetes mellitus using a one-group, pretest-posttest quasi-experimental design. Compliance with the program was 100%. Significant reductions in total calorie intake as well as body mass index were achieved, with an increase in the percentage of subjects achieving better diabetes control as measured by the 2-hr hemastix. Improvements in diabetes knowledge and disease-specific and generic measures of quality of life were also observed. Most subjects evaluated this mode of service delivery favorably in the questionnaire and focus group discussions. There is potential for the integration of this mode of service delivery into current health services.

Diatoms are unicellular algae with plastids acquired by secondary endosymbiosis. They are responsible for approximately 20% of global carbon fixation. We report the 34 million-base pair draft nuclear genome of the marine diatom Thalassiosira pseudonana and its 129 thousand-base pair plastid and 44 thousand-base pair mitochondrial genomes. Sequence and optical restriction mapping revealed 24 diploid nuclear chromosomes. We identified novel genes for silicic acid transport and formation of silica-based cell walls, high-affinity iron uptake, biosynthetic enzymes for several types of polyunsaturated fatty acids, use of a range of nitrogenous compounds, and a complete urea cycle, all attributes that allow diatoms to prosper in aquatic environments.